Epigenetics and the Environment

Genomic imprinting is an example of a _________ of ___________ effect, where the phenotypic expression of an allele is dependent on inheritance from the maternal or paternal side

This is a parent-of-origin effect where the same growth gene inherited from a ____ lion that promotes growth, supresses growth when inherited from a _____.
- Liger = BIG , Tigon = SMALL

Recent evidence supports the _________ ________ hypothesis in humans:
- Newly discovered BIPOLAR effects: The same allele inherited from a different parent pulls the traits in opposite directions
- Ex: The same gene increased diabetes risk by 9% inherited from Dad, and decreased risk by 14% when inherited by Mom.

This is the measure of all non-genetic, environmental exposures an individual experiences from conception to death, along with how the body biologically responds to them
"The totality of human environmental exposure"

Categories of the Exposome:

(1) ___________ external environment: Your immediate surroundings and daily lifestyle choices (diet, exercise, tobacco/alcohol use, caffiene, medication, etc.)

(2) ___________ external environmet: Broad conditions that are often shared across communities/popultions (climate, urban environment, traffic, etc.)

(3) ___________ environment: Biological environment inside your body (Hormones, body systems, microbiome, genes, proteins)

__________ of Exposure:
(1) Diet and Supplements: food, drink, medication (neccessity)
(2) Smoking and alcohol behaviors: our choices
(3) Chemical contaminants in the air
(4) Stress: Socioeconomic status, racial injustice, personal circumstances

________ of Exposure:
(1) Inhalation
(2) Digestion
(3) Dermal absorption
(4) Intraveneous/intramuscular
(5) Transplacental

Measuring Environmental Exposure:

(1) Data gathering: Participant questionares/surveys, personal monitors, outdoor/satellite monitors, and spatial monitoring

(2) ________ dose: Environmental sampline and chemical measures (water, air, soil samples)

(2) _________ dose: Biological sampling and chemical/metabolite measures (blood or urine samples, biopsy)

These are alles at a loci with VARIABLE methylation status between individuals without underlying genetic differences

Ex: mom (G1) has a somewhat methylated loci for a Trp53, but her offspring could all have different methylation patterns (no methylation, complete methylation, somewhat, etc.)

Metastable Epialleles are used as _________, useful tools to study the impact of environmental conditions on DNA methylation

Metastable Epialleles: The Agouti Viable Yellow Mouse Model

- The Avy locus contains 2 promoters:
(1) The normal promoter = generates ________ coat color
(2) The IAP insertion upstream of the normal promoter = generates yellow coat color
- The IAP contains a ___ rich region and a degree of methylation that is proportional to darkness of coat color

Agouti Mice: Metastable Epialleles

1) If the IAP is methylated, which promoter will be used?

2) What color will the mouse be if the IAP is methylated?

3) What color will the mouse be if the IAP is unmethylated?

Avy mice are an experimental tool used as biosensors for environmental impacts on DNA __________
- First generation females are subject to environmental exposures, and offspring are counted and categorized for coat color
<-----Yellow------------mixed------------Brown----->
------(__________)------------------------(hypermethylation)

This is a biological phenomenon where a low dose of a stressor triggers a beneficial, adaptive response in a cell or organism, while a high dosage causes damage or toxicity
- Ex: Lead in Avy (low dose = _________) v. (high does = ____________)

The Axin Fused (AxinFu) Mouse

- Loss of methylation at the IAP causes the expression of the ___________ transcript of a certain protien, which leads to a ______ tail phenotype

Metastable Epialleles in Humans: Season of Conception
- Individuals concieved in the DRY season are significantly more likely to exhibit hypomethylation at this locus than individuals concieved during the RAINY season
- This suggests that __________ availability affects epigenotype

The Developmental Origins of Health and Disease (DOHaD) Hypothesis

- The methylation state at the metastable epialleles is established in early development
- After establishment in early development, all ______ cells have the same methylation profile, so the epigenetic state is maintained through cell division
-- This property makes epigenetic marks strong candidates for linking ____ life environmental stress to later life disease
- Even subtle environmentally induced changes in early development can have long lasting and impactful effects on health later in life

These are regions of DNA with consistent methylation status over the entire lifespan

Newborn Epigenetic Study (NEST): Cadmium
- Hypothesis: Epigenetic programming links parental factors to obesity and other chronic diseases in children
- Methods: Maternal blood and newborn ____ blood was collected, and methylation status was analyzed

- Findings: Differenetially methylated regions (DMRs) identified in newborn cord blood overlapped with DMRs in maternal blood due to cadmium
- ICRs appear more sensitive to _________ exposure than other areas of the genome

Diethylstilbestrol: Non-steroidal estrogen used from the 1940s to the 1070s to prevent miscarriage
- Affects _ generations

______________ Disadvantage: E-risk longitudinal twin study conducted in the UK

- Collected data on a neighborhoods' disadvantages (4Ds) across childhood
- Scientists linked the 4Ds to differential methylation in genes realted to inflammation and smoking, even when adjusting for whether or not those individuals smoked or had the inflammation phenotype)
- They reported this using a POLYEPIGENETIC SCORE: Aggregates data across multiple CpGs that have been linked to the same outcome

Take Home Messages:

(1) Various processes are mediated by epigenetic mechanisms: __________ imprinting and parental __________ hypothesis

(2) Exposures occur throughout your life: C__________ and Diethylstilbestrol

(3) Developmental exposures can lead to health issues later in life, how (hypothesis)?